Special Topic Changing Role of Hyaluronidase in Plastic Surgery Steven H. Bailey, M.D. Steven Fagien, M.D. Rod J. Rohrich, M.D. Dallas, Texas
Summary: Soft-tissue augmentation has become an increasingly popular option for facial rejuvenation. Hyaluronic acid fillers are part of the most rapidly expanding segment of this market, largely because of their safe drug profile and temporary nature. Despite their good safety profile, they can and do have complications ranging from superficial placement, uneven placement, granulomatous reactions, and skin necrosis. This article reviews the on- and off-label uses of hyaluronidase and presents several clinical algorithms detailing the effective and safe use of hyaluronidase to manage complications secondary to hyaluronic acid fillers. (Plast. Reconstr. Surg. 133: 127e, 2014.)
U
se of soft-tissue fillers has become, and still is, one of the most popular aesthetic procedures in the United States for patients requesting nonsurgical facial rejuvenation, according to the American Society of Plastic Surgeons.1 Fillers come in several varieties and have differing properties. The filling agents fall into two major categories: (1) permanent and (2) temporary. Currently, the most commonly used fillers are temporary fillers, among which the hyaluronic acid–based fillers are the most popular. Their popularity stems primarily from their safe drug profile and their temporary nature. Hyaluronic acid is a glycosaminoglycan biopolymer of alternating d-glucuronic acid and N-acetyl-d-glucosamine monosaccharide residues cross-linked into long, repeated, unbranched polyanionic chains.2 It is ubiquitous in the dermis of mammalian skin and its viscoelastic properties aid in performing the functions of lubrication and shock absorption, and adding bulk to the dermis by increasing dermal hydration. Despite its being a natural part of the extracellular matrix of the dermis, and despite its popularity among clinicians, hyaluronic acid–based fillers do have complications. The typical complications seen with hyaluronic acid–based fillers are primarily technique based and consist of superficial placement, uneven placement, granulomatous reactions, and skin necrosis.3 Because of the temporary nature of the hyaluronic From the Department of Plastic Surgery, University of Texas Southwestern Medical Center. Received for publication March 24, 2013; accepted April 25, 2013. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0b013e3182a4c282
acid fillers, most complications will resolve with time; however, severe complications (i.e., severe infections, severe cosmetic deformities, and impending vascular compromise) require more aggressive treatment with adjunctive agents such as hyaluronidase. The purpose of this study is to review injectable hyaluronidase formulations that are currently commercially available, to compare and contrast the formulations and safety profiles, and to propose an algorithm as to their safe use in the clinical setting.
BACKGROUND Hyaluronidase is a naturally occurring enzyme that, as its name implies, degrades the substrate hyaluronic acid. Hyaluronidase breaks down hyaluronic acid, by separating the 1,4-glucosaminidic bond between C1 of the glucosamine moiety and C4 of the glucuronic acid. In its natural environment, hyaluronidase facilitates several important functions, ranging from fertility4 to bacterial pathogenesis.5,6 On injection, hyaluronidase immediately disperses in tissues, and rapid return to previous skin contour is achieved.7 The duration of hyaluronidase enzyme activity is dependent on location. Hyaluronidase acts immediately once in contact with its substrate, and the duration of activity is typically 24 to 48 hours in dermal tissues.8 However, it has an extended duration in ocular tissues that ranges from 60 to 112 hours.9 In contrast, the hyaluronidase enzyme is deactivated immediately when injected intravenously. It Disclosure: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this article.
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Plastic and Reconstructive Surgery • February 2014 is hypothesized that the process is antibody mediated; however, the true mechanism of deactivation is unknown.10–13
USES OF HYALURONIDASE Uses of hyaluronidase have changed throughout its existence. The current U.S. Food and Drug Administration–approved indications are (1) for hypodermoclysis14,15; (2) to increase subcutaneous drug absorption (of beneficial drugs), disperse harmful injected drugs, and treat extravasation injury16–18 (Table 1); and (3) for subcutaneous urography to improve resorption of radiopaque agents.10–13 Current off-label uses include dissolution of misplaced hyaluronic acid–based fillers, treatment of granulomatous foreign-body reaction, and injection-related necrosis. Hypodermoclysis Hypodermoclysis is a method of infusing fluid into subcutaneous tissue for rehydration. Table 1. Extravasated Agents Treated with Hyaluronidase* Additives Calcium salts Dextrose solution, 10% Lipid emulsion Potassium solutions Sodium bicarbonate solution Total parenteral nutrition solution Tromethamine Antibiotics Amphotericin Cloxacillin Erythromycin Gentamicin Vancomycin Anticonvulsants Phenytoin Antidiuretics Mannitol Bronchodilators Aminophylline Benzodiazepine Diazepam Chemotherapeutic agents Vinblastine Vincristine Contrast Contrast media Radiolabeled contrast media *From Bellin MF, Jakobsen JA, Tomassin I, et al. Contrast medium extravasation injury: Guidelines for prevention and management. Eur Radiol. 2002;12:2807–2812; Marcia L, Buck PD. Treatment of intravenous extravasations. Pediatr Pharmacother. 1998;4:1–2; Zimmet SE. Hyaluronidase in the prevention of sclerotherapy-induced extravasation necrosis: A dose-response study. Dermatol Surg. 1996;22:73–76; Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous phenytoin extravasation. J Child Neurol. 1998;13:246– 247; and Kumar MM, Sprung J. The use of hyaluronidase to treat mannitol extravasation. Anesth Analg. 2003;97:1199–1200.
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This process is often limited by the volume of subcutaneous compartments. Early reports in the literature note the use of hyaluronidase as an adjunctive agent for subcutaneous rehydration in elderly patients.14 It is hypothesized that hyaluronidase or a factor within the hyaluronidase causes enhanced capillary permeability.19 Several studies in the elderly population have shown safe administration of 1.5 liters of normal saline or half-normal saline with additives (in combination with hyaluronidase) over a 24-hour period in one location or up to 3 liters using two separate locations. In addition, when compared with intravenous administration of normal saline at a rate of 167 cc/hr, subcutaneous infiltration of radioisotopic tritiated water and technetium pertechnetate showed no difference in absorption and no residual radioactivity in the subcutaneous tissue after 75 minutes.20 Drug Absorption/Management of Extravasation Injuries Intravenous infiltration and extravasation injuries are relatively uncommon occurrences in the hospital and other health care environments; however, their effects can be devastating (i.e., skin ulceration, soft-tissue necrosis, and compartment syndrome). Hyaluronidase has been used as an adjunct in the treatment of extravasation injuries. It is largely indicated in cases where reduction of the concentration of extravasate will reduce the risk of injury. Injected hyaluronidase has been shown to reduce complications of several commonly used agents (Table 1).21–25 It should be administered within 1 hour of extravasation to obtain quick dissipation of the skin swelling; recommended dosages range from 15 to 250 units diluted in 1.5 to 6 ml of fluid. Urography Urography is often used in the pediatric population to diagnose anatomical anomalies of the genitourinary systems. Administration of intravenous contrast in this age group can be particularly challenging because of smaller caliber veins and smaller subcutaneous compartments, with increased risk of infiltration and compartment syndrome. The use of hyaluronidase infiltration with dye for the purpose of urography was introduced in the 1950s as an alternative to intravenous infiltration. Adequate visualization has been achieved with administration of 0.8 mg of hyaluronidase subcutaneously before administering the contrast medium (diodrast 10 to 15 ml of a 35% solution diluted in 35 to 75 ml of saline).26
Volume 133, Number 2 • Changing Role of Hyaluronidase OFF-LABEL USES (USES IN PLASTIC SURGERY) Hyaluronic acid’s hygroscopic properties attract water and allow for reliable, reproducible facial contouring. Unfortunately, when hyaluronic acids are placed in a superficial or inappropriate location, several undesirable side effects can occur, namely, the bluish discoloration resulting from the Tyndall effect or excess deposition, granulomatous foreign-body reaction, and injection necrosis. Treatment of Misplaced/Excess Hyaluronic Acid Superficial or excess deposition of hyaluronic fillers occurs mainly when a novice or inexperienced injector places the filler in the epidermis or superficial dermis. The excess placement can cause lumps or telltale injection lines. In addition, superficial deposition can result in scattering of light within the fine particulate hyaluronic acid medium, resulting in a bluish gray discoloration of the skin known as the Tyndall effect. Therapeutic treatment options include waiting for the filler to break down, aspiration/incision, and expression. The latest treatment option is use of hyaluronidase to neutralize/increase the breakdown of the hyaluronic acid. Lambros and Soparkar et al. described the use of hyaluronidase for treatment of superficial hyaluronic acid fillers in small case reports in 2004.27,28 These reports demonstrated resolution of more than 90 percent of the lumpiness within 1 week. The usefulness of hyaluronidase as a treatment for superficial placement of hyaluronic acid was confirmed by Vartanian et al. in 2005 in a prospective, randomized study.29 Currently, there is no standard dosing for treatment of misplaced or excess hyaluronic acid deposition. This is partly because injectable hyaluronic acids have different sensitivities to degradation by hyaluronidase, and hyaluronidase allergic reactions may be somewhat dose dependent. Sall and Férard demonstrated that Juvéderm 24 HV (Allergan, Inc., Irvine, Calif.), for example, is approximately 50 percent less susceptible to enzymatic degradation by bovine hyaluronidase than Restylane (Medicis, a division of Valeant Pharmaceuticals, Inc., Scottsdale, Ariz.).30 Case reports have demonstrated efficacy with dosing of up to 75 to 150 units of hyaluronidase; however, higher dosing regimens have been associated with allergic reactions.29 These allergic reactions include redness and angioedema and even anaphylaxis. Studies advocating lower dosing demonstrated
lower rates of allergic reactions.8 We recommend starting with small doses of 5 to 15 units per site, with repeated treatment 2 weeks later if needed to minimize the chance of an allergic reaction. In patients with previous allergic reactions, further investigation is needed before treatment. Treatment of patients with bee-sting allergies should be avoided because of a risk of cross-reactivity to the hyaluronidase. In addition, patients with allergic reaction to bovine collagen should not be treated with bovine-based hyaluronidase. Treatment of Granulomatous Reaction Granulomatous reactions to dermal fillers are another fortunately rare complication that can occur with dermal fillers. These reactions were well described by Brody and several other authors.8,31,32 They typically occur within 1 week after injection and present as multiple warm, red, indurated nodules in the area of treatment. The nodules yield negative culture results and produce only clear nonpurulent fluid on incision. Although the cause is not clearly defined, it is speculated that the reaction is either immunoglobulin E/immunoglobulin G mediated as a response to the protein or contaminant within the hyaluronic acid filler.8,33 Prior treatment modalities consisted of oral antibiotics, steroid tapers, topical steroids, and tacrolimus, all with minimal effect. Hyaluronidase is currently the treatment of choice, and Brody, Cohen, and others have detailed its efficacy in resolving granulomatous reactions in a dose-dependent manner (i.e., single high-dose injection, with resolution in 24 hours; or multiple lower dosage injections, with resolution in up to 2 weeks). Intralesional injection of 15 to 75 units of hyaluronidase mixed with 1% lidocaine with epinephrine has been recommended, with lower dosages being associated with a decreased incidence of allergic reaction.8,28,29,31 Treatment of Injection-Related Necrosis Injection-site necrosis is also a rare but serious adverse effect of hyaluronic acid. This phenomenon has been described by Hirsch et al., Glaich et al., and others as necrosis or threatened necrosis in an area of injection.34–36 The algorithm offered by Hirsch et al. included two 325-mg enteric-coated aspirin, alternating topical nitroglycerin paste, and hot compresses to the affected area. In addition, 30 units of hyaluronidase is injected along the course of the artery involved.36 The patient showed resolution in 8 hours and, at 2 weeks, had no evidence of compromise.
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Plastic and Reconstructive Surgery • February 2014 HYALURONIDASE PREPARATIONS Hyaluronidase comes in several forms. The major categories are human recombinant and nonhuman (bovine and ovine). The preparations are similar, with the exception of source, preservative, concentration, and price; these differences are summarized in Table 2. Hyaluronidase preparations are very safe and have similar side-effect profiles, with a 0.1% rate of anaphylactic reaction. Because of this rate of anaphylaxis, patients should be given a test dose before full treatment.
USES OF HYALURONIDASE Use of injectables (botulinum toxin type A and fillers) for facial rejuvenation has become very popular. Hyaluronic acid–based fillers are rapidly increasing their market share year after year, primarily because of their good safety profile and predictable results. Careful injection technique and detailed knowledge of anatomy and filler can avoid many common complications. However, once complications occur, the provider should have a routine algorithm to resolve the complication or reduce the risk of harm to the patient.
ERRONEOUS PLACEMENT Superficial placement and/or excess placement occurs when filler is injected into the superficial dermis or too much filler is injected into one location. Superficial injection can occur if the visual cues are ignored during injection. Excess placement can be avoided by smooth, even deposition of filler. The easiest method is to develop a systematic method of placing filler to cover an area through linear threading, fanning, serial puncture, or crosshatching.3 If erroneous placement occurs, massage can often be used to spread/mold the filler to a more even shape. If massage does not help, a commercially available hyaluronidase of the provider’s choosing can be used to remove the hyaluronic acid filler. Hyaluronidase disperses rapidly in tissues, and in the dermis its activity is limited to 48 hours. It is these two properties that allow rapid degradation of
misplaced hyaluronic acid without risk of additional contour deformity.
GRANULOMATOUS INFECTION Hyaluronic acid–associated granulomatous infections typically present as red, nonpurulent bumps in the distribution of previous hyaluronic acid deposition. These infections can be treated initially with antibiotics and topical steroids, especially if the patient desires to maintain the fullness from the hyaluronic acid filler. However, if the infection is severe or the patient would like more immediate resolution, use of high-dose hyaluronidase has been shown to be effective.
IMPENDING NECROSIS Skin necrosis is the most severe of the complications that can occur with hyaluronic acid injection. To prevent vascular compromise, it is incumbent on the clinician to be aware of the anatomy and avoid inadvertent intraarterial or juxtaarterial injection. If vascular compromise occurs, time is of the essence to prevent necrosis. In addition to supportive measures (i.e., acetylsalicylic acid, warm compress, and nitroglycerin), 30 units of hyaluronidase should be injected along the course of the involved artery to allow restoration of flow (Fig. 1).
CONCLUSIONS Hyaluronic acid is a ubiquitous glycosaminoglycan that has been used for facial rejuvenation. Its popularity stems from its good safety profile and the ability to achieve reproducible results. Despite the safety of these agents, side effects can occur. Until the early 2000s, the clinician’s recourse for malplacement of hyaluronic acid fillers was massage, incision and drainage, oral antibiotics, oral steroids, and a tincture of time. Now, with the addition of hyaluronidase, clinicians have a safe and effective way of essentially erasing the effects of hyaluronic acid fillers. The rapid response of hyaluronidase can be particularly helpful in situations of skin compromise or even in the event of malposition or
Table 2. Comparison of Hyaluronidase Preparations Trade Name Amphadase Hydase Vitrase Hylenex
Source of Hyaluronidase Bovine Bovine Ovine Human recombinant
Date of FDA Approval
Currently Available
Available Dosage Form
October 26, 2004 No (2010) 150 USP units per ml, 2-ml vial October 25, 2005 No (2008) 150 USP units per ml, 2-ml vial May 5, 2004 Yes 200 USP units per ml, 2-ml vial December 2, 2005 Yes 150 USP units per ml, 2-ml vial
FDA, U.S. Food and Drug Administration; USP, U.S. Pharmacopeial Convention; N/A, not applicable.
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Preservative
Cost
Thimerosal N/A N/A N/A
N/A N/A $60.40/vial $51.67/vial
Volume 133, Number 2 • Changing Role of Hyaluronidase
Fig. 1. Impending skin necrosis. ASA, acetylsalicylic acid.
overfilling. Because of its good safety profile and effectiveness, clinicians using hyaluronic acid fillers should keep a hyaluronidase of their choosing on site to thwart the most severe complications. Rod J. Rohrich, M.D. Department of Plastic Surgery University of Texas Southwestern Medical Center 1801 Inwood Road Dallas, Texas 75390-9132 [email protected]
REFERENCES 1. American Society of Plastic Surgeons. 2011 Plastic Surgery Procedural Statistics. Available at: http://www.plasticsurgery.org/Documents/news-resources/statistics/2011-statistics/2011_Stats_Full_Report.pdf. Accessed September 16, 2012. 2. Girish KS, Kemparaju K. The magic glue hyaluronan and its eraser hyaluronidase: A biological overview. Life Sci. 2007;80:1921–1943. 3. Rohrich RJ, Ghavami A, Crosby MA. The role of hyaluronic acid fillers (Restylane) in facial cosmetic surgery: Review and technical considerations. Plast Reconstr Surg. 2007;120:41S–54S. 4. Marković-Housley Z, Miglierini G, Soldatova L, Rizkallah PJ, Müller U, Schirmer T. Crystal structure of hyaluronidase, a major allergen of bee venom. Structure 2000;8:1025–1035. 5. Starr CR, Engleberg NC. Role of hyaluronidase in subcutaneous spread and growth of group A streptococcus. Infect Immun. 2006;74:40–48. 6. Zukaite V, Biziulevicius GA. Acceleration of hyaluronidase production in the course of batch cultivation of Clostridium perfringens can be achieved with bacteriolytic enzymes. Lett Appl Microbiol. 2000;30:203–206. 7. Lewis-Smith PA. Adjunctive use of hyaluronidase in local anaesthesia. Br J Plast Surg. 1986;39:554–558. 8. Brody HJ. Use of hyaluronidase in the treatment of granulomatous hyaluronic acid reactions or unwanted hyaluronic acid misplacement. Dermatol Surg. 2005;31:893–897. 9. Kuppermann BD, Thomas EL, de Smet MD, et al. Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly
purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol. 2005;140:573–584. 10. Amphastar Pharmaceuticals. Amphadase (hyaluronidase) package insert. Rancho Cucamonga, Calif: Amphastar Pharmaceuticals, Inc.; 2005. 11. Baxter Healthcare. Hylenex (hyaluronidase) package insert. San Diego, Calif: Baxter Healthcare Corp; 2006. 12. PrimaPharm. Hydase (hyaluronidase) package insert. San Diego, Calif: PrimaPharm; 2005. 13. ISTA Pharmaceuticals. Vitrase (hyaluronidase) package insert. Irvine, Calif.: ISTA Pharmaceuticals, Inc.; 2007. 14. Constans T, Dutertre JP, Frogé E. Hypodermoclysis in dehydrated elderly patients: Local effects with and without hyaluronidase. J Palliat Care 1991;7:10–12. 15. Pirrello RD, Ting Chen C, Thomas SH. Initial experiences with subcutaneous recombinant hyaluronidase. J Palliat Med. 2007;10:861–864. 16. Kallio H, Paloheimo M, Maunuksela EL. Hyaluronidase as an adjuvant in bupivacaine-lidocaine mixture for retrobulbar/peribulbar block. Anesth Analg. 2000;91:934–937. 17. Smith KJ, Skelton HG, Turiansky G, et al. Hyaluronidase enhances the therapeutic effect of vinblastine in intralesional treatment of Kaposi’s sarcoma. J Am Acad Dermatol. 1997;36:239–242. 18. Bocci V, Muscettola M, Naldini A, Bianchi E, Segre G. The lymphatic route: II. Pharmacokinetics of human recombinant interferon-alpha 2 injected with albumin as a retarder in rabbits. Gen Pharmacol. 1986;17:93–96. 19. Houck J, Chang C. Permeability factor contaminating hyaluronidase preparations. Inflammation 1979;3:447–451. 20. Sasson M, Shvartzman P. Hypodermoclysis: An alternative infusion technique. Am Fam Physician 2001;64:1575–1578. 21. Bellin MF, Jakobsen JA, Tomassin I, et al. Contrast medium extravasation injury: Guidelines for prevention and management. Eur Radiol. 2002;12:2807–2812. 22. Marcia L, Buck PD. Treatment of intravenous extravasations. Pediatr Pharmacother. 1998;4:1–2. 23. Zimmet SE. Hyaluronidase in the prevention of sclerotherapy-induced extravasation necrosis: A dose-response study. Dermatol Surg. 1996;22:73–76. 24. Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous phenytoin extravasation. J Child Neurol. 1998;13:246–247.
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Plastic and Reconstructive Surgery • February 2014 25. Kumar MM, Sprung J. The use of hyaluronidase to treat mannitol extravasation. Anesth Analg. 2003;97:1199–1200. 26. Burket LC, György P. Clinical observations on the use of hyaluronidase. Pediatrics 1949;3:56–63. 27. Lambros V. The use of hyaluronidase to reverse the effects of hyaluronic acid filler. Plast Reconstr Surg. 2004;114:277. 28. Soparkar CN, Patrinely JR, Tschen J. Erasing restylane. Ophthal Plast Reconstr Surg. 2004;20:317–318, 29. Vartanian AJ, Frankel AS, Rubin MG. Injected hyaluronidase reduces restylane-mediated cutaneous augmentation. Arch Facial Plast Surg. 2005;7:231–237. 30. Sall I, Férard G. Comparison of the sensitivity of 11 crosslinked hyaluronic acid gels to bovine testis hyaluronidase. Polym Degrad Stab. 2007;92:915–919. 31. Bailey SH, Cohen JL, Kenkel JM. Etiology, prevention, and treatment of dermal filler complications. Aesthet Surg J. 2011;31:110–121.
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32. Cohen JL. Understanding, avoiding, and managing der mal filler complications. Dermatol Surg. 2008;34(Suppl 1):S92–S99. 33. Klein AW. Granulomatous foreign body reaction against hyaluronic acid. Dermatol Surg. 2004;30:1070. 34. Inoue K, Sato K, Matsumoto D, Godna K, Yoshimura K. Arterial embolization and skin necrosis of the nasal ala following injection of dermal fillers. Plast Reconstr Surg. 2008;121:127e–128e. 35. Glaich AS, Cohen JL, Goldberg LH. Injection necrosis of the glabella: Protocol for prevention and treatment after use of dermal fillers. Dermatol Surg. 2006;32:276–281. 36. Hirsch RJ, Cohen JL, Carruthers JD. Successful management of an unusual presentation of impending necrosis following a hyaluronic acid injection embolus and a proposed algorithm for management with hyaluronidase. Dermatol Surg. 2007;33:357–360.
Summary: Soft-tissue augmentation has become an increasingly popular option for facial rejuvenation. Hyaluronic acid fillers are part of the most rapidly expanding segment of this market, largely because of their safe drug profile and temporary nature. Despite their good safety profile, they can and do have complications ranging from superficial placement, uneven placement, granulomatous reactions, and skin necrosis. This article reviews the on- and off-label uses of hyaluronidase and presents several clinical algorithms detailing the effective and safe use of hyaluronidase to manage complications secondary to hyaluronic acid fillers. (Plast. Reconstr. Surg. 133: 127e, 2014.)
U
se of soft-tissue fillers has become, and still is, one of the most popular aesthetic procedures in the United States for patients requesting nonsurgical facial rejuvenation, according to the American Society of Plastic Surgeons.1 Fillers come in several varieties and have differing properties. The filling agents fall into two major categories: (1) permanent and (2) temporary. Currently, the most commonly used fillers are temporary fillers, among which the hyaluronic acid–based fillers are the most popular. Their popularity stems primarily from their safe drug profile and their temporary nature. Hyaluronic acid is a glycosaminoglycan biopolymer of alternating d-glucuronic acid and N-acetyl-d-glucosamine monosaccharide residues cross-linked into long, repeated, unbranched polyanionic chains.2 It is ubiquitous in the dermis of mammalian skin and its viscoelastic properties aid in performing the functions of lubrication and shock absorption, and adding bulk to the dermis by increasing dermal hydration. Despite its being a natural part of the extracellular matrix of the dermis, and despite its popularity among clinicians, hyaluronic acid–based fillers do have complications. The typical complications seen with hyaluronic acid–based fillers are primarily technique based and consist of superficial placement, uneven placement, granulomatous reactions, and skin necrosis.3 Because of the temporary nature of the hyaluronic From the Department of Plastic Surgery, University of Texas Southwestern Medical Center. Received for publication March 24, 2013; accepted April 25, 2013. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0b013e3182a4c282
acid fillers, most complications will resolve with time; however, severe complications (i.e., severe infections, severe cosmetic deformities, and impending vascular compromise) require more aggressive treatment with adjunctive agents such as hyaluronidase. The purpose of this study is to review injectable hyaluronidase formulations that are currently commercially available, to compare and contrast the formulations and safety profiles, and to propose an algorithm as to their safe use in the clinical setting.
BACKGROUND Hyaluronidase is a naturally occurring enzyme that, as its name implies, degrades the substrate hyaluronic acid. Hyaluronidase breaks down hyaluronic acid, by separating the 1,4-glucosaminidic bond between C1 of the glucosamine moiety and C4 of the glucuronic acid. In its natural environment, hyaluronidase facilitates several important functions, ranging from fertility4 to bacterial pathogenesis.5,6 On injection, hyaluronidase immediately disperses in tissues, and rapid return to previous skin contour is achieved.7 The duration of hyaluronidase enzyme activity is dependent on location. Hyaluronidase acts immediately once in contact with its substrate, and the duration of activity is typically 24 to 48 hours in dermal tissues.8 However, it has an extended duration in ocular tissues that ranges from 60 to 112 hours.9 In contrast, the hyaluronidase enzyme is deactivated immediately when injected intravenously. It Disclosure: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this article.
www.PRSJournal.com
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Plastic and Reconstructive Surgery • February 2014 is hypothesized that the process is antibody mediated; however, the true mechanism of deactivation is unknown.10–13
USES OF HYALURONIDASE Uses of hyaluronidase have changed throughout its existence. The current U.S. Food and Drug Administration–approved indications are (1) for hypodermoclysis14,15; (2) to increase subcutaneous drug absorption (of beneficial drugs), disperse harmful injected drugs, and treat extravasation injury16–18 (Table 1); and (3) for subcutaneous urography to improve resorption of radiopaque agents.10–13 Current off-label uses include dissolution of misplaced hyaluronic acid–based fillers, treatment of granulomatous foreign-body reaction, and injection-related necrosis. Hypodermoclysis Hypodermoclysis is a method of infusing fluid into subcutaneous tissue for rehydration. Table 1. Extravasated Agents Treated with Hyaluronidase* Additives Calcium salts Dextrose solution, 10% Lipid emulsion Potassium solutions Sodium bicarbonate solution Total parenteral nutrition solution Tromethamine Antibiotics Amphotericin Cloxacillin Erythromycin Gentamicin Vancomycin Anticonvulsants Phenytoin Antidiuretics Mannitol Bronchodilators Aminophylline Benzodiazepine Diazepam Chemotherapeutic agents Vinblastine Vincristine Contrast Contrast media Radiolabeled contrast media *From Bellin MF, Jakobsen JA, Tomassin I, et al. Contrast medium extravasation injury: Guidelines for prevention and management. Eur Radiol. 2002;12:2807–2812; Marcia L, Buck PD. Treatment of intravenous extravasations. Pediatr Pharmacother. 1998;4:1–2; Zimmet SE. Hyaluronidase in the prevention of sclerotherapy-induced extravasation necrosis: A dose-response study. Dermatol Surg. 1996;22:73–76; Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous phenytoin extravasation. J Child Neurol. 1998;13:246– 247; and Kumar MM, Sprung J. The use of hyaluronidase to treat mannitol extravasation. Anesth Analg. 2003;97:1199–1200.
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This process is often limited by the volume of subcutaneous compartments. Early reports in the literature note the use of hyaluronidase as an adjunctive agent for subcutaneous rehydration in elderly patients.14 It is hypothesized that hyaluronidase or a factor within the hyaluronidase causes enhanced capillary permeability.19 Several studies in the elderly population have shown safe administration of 1.5 liters of normal saline or half-normal saline with additives (in combination with hyaluronidase) over a 24-hour period in one location or up to 3 liters using two separate locations. In addition, when compared with intravenous administration of normal saline at a rate of 167 cc/hr, subcutaneous infiltration of radioisotopic tritiated water and technetium pertechnetate showed no difference in absorption and no residual radioactivity in the subcutaneous tissue after 75 minutes.20 Drug Absorption/Management of Extravasation Injuries Intravenous infiltration and extravasation injuries are relatively uncommon occurrences in the hospital and other health care environments; however, their effects can be devastating (i.e., skin ulceration, soft-tissue necrosis, and compartment syndrome). Hyaluronidase has been used as an adjunct in the treatment of extravasation injuries. It is largely indicated in cases where reduction of the concentration of extravasate will reduce the risk of injury. Injected hyaluronidase has been shown to reduce complications of several commonly used agents (Table 1).21–25 It should be administered within 1 hour of extravasation to obtain quick dissipation of the skin swelling; recommended dosages range from 15 to 250 units diluted in 1.5 to 6 ml of fluid. Urography Urography is often used in the pediatric population to diagnose anatomical anomalies of the genitourinary systems. Administration of intravenous contrast in this age group can be particularly challenging because of smaller caliber veins and smaller subcutaneous compartments, with increased risk of infiltration and compartment syndrome. The use of hyaluronidase infiltration with dye for the purpose of urography was introduced in the 1950s as an alternative to intravenous infiltration. Adequate visualization has been achieved with administration of 0.8 mg of hyaluronidase subcutaneously before administering the contrast medium (diodrast 10 to 15 ml of a 35% solution diluted in 35 to 75 ml of saline).26
Volume 133, Number 2 • Changing Role of Hyaluronidase OFF-LABEL USES (USES IN PLASTIC SURGERY) Hyaluronic acid’s hygroscopic properties attract water and allow for reliable, reproducible facial contouring. Unfortunately, when hyaluronic acids are placed in a superficial or inappropriate location, several undesirable side effects can occur, namely, the bluish discoloration resulting from the Tyndall effect or excess deposition, granulomatous foreign-body reaction, and injection necrosis. Treatment of Misplaced/Excess Hyaluronic Acid Superficial or excess deposition of hyaluronic fillers occurs mainly when a novice or inexperienced injector places the filler in the epidermis or superficial dermis. The excess placement can cause lumps or telltale injection lines. In addition, superficial deposition can result in scattering of light within the fine particulate hyaluronic acid medium, resulting in a bluish gray discoloration of the skin known as the Tyndall effect. Therapeutic treatment options include waiting for the filler to break down, aspiration/incision, and expression. The latest treatment option is use of hyaluronidase to neutralize/increase the breakdown of the hyaluronic acid. Lambros and Soparkar et al. described the use of hyaluronidase for treatment of superficial hyaluronic acid fillers in small case reports in 2004.27,28 These reports demonstrated resolution of more than 90 percent of the lumpiness within 1 week. The usefulness of hyaluronidase as a treatment for superficial placement of hyaluronic acid was confirmed by Vartanian et al. in 2005 in a prospective, randomized study.29 Currently, there is no standard dosing for treatment of misplaced or excess hyaluronic acid deposition. This is partly because injectable hyaluronic acids have different sensitivities to degradation by hyaluronidase, and hyaluronidase allergic reactions may be somewhat dose dependent. Sall and Férard demonstrated that Juvéderm 24 HV (Allergan, Inc., Irvine, Calif.), for example, is approximately 50 percent less susceptible to enzymatic degradation by bovine hyaluronidase than Restylane (Medicis, a division of Valeant Pharmaceuticals, Inc., Scottsdale, Ariz.).30 Case reports have demonstrated efficacy with dosing of up to 75 to 150 units of hyaluronidase; however, higher dosing regimens have been associated with allergic reactions.29 These allergic reactions include redness and angioedema and even anaphylaxis. Studies advocating lower dosing demonstrated
lower rates of allergic reactions.8 We recommend starting with small doses of 5 to 15 units per site, with repeated treatment 2 weeks later if needed to minimize the chance of an allergic reaction. In patients with previous allergic reactions, further investigation is needed before treatment. Treatment of patients with bee-sting allergies should be avoided because of a risk of cross-reactivity to the hyaluronidase. In addition, patients with allergic reaction to bovine collagen should not be treated with bovine-based hyaluronidase. Treatment of Granulomatous Reaction Granulomatous reactions to dermal fillers are another fortunately rare complication that can occur with dermal fillers. These reactions were well described by Brody and several other authors.8,31,32 They typically occur within 1 week after injection and present as multiple warm, red, indurated nodules in the area of treatment. The nodules yield negative culture results and produce only clear nonpurulent fluid on incision. Although the cause is not clearly defined, it is speculated that the reaction is either immunoglobulin E/immunoglobulin G mediated as a response to the protein or contaminant within the hyaluronic acid filler.8,33 Prior treatment modalities consisted of oral antibiotics, steroid tapers, topical steroids, and tacrolimus, all with minimal effect. Hyaluronidase is currently the treatment of choice, and Brody, Cohen, and others have detailed its efficacy in resolving granulomatous reactions in a dose-dependent manner (i.e., single high-dose injection, with resolution in 24 hours; or multiple lower dosage injections, with resolution in up to 2 weeks). Intralesional injection of 15 to 75 units of hyaluronidase mixed with 1% lidocaine with epinephrine has been recommended, with lower dosages being associated with a decreased incidence of allergic reaction.8,28,29,31 Treatment of Injection-Related Necrosis Injection-site necrosis is also a rare but serious adverse effect of hyaluronic acid. This phenomenon has been described by Hirsch et al., Glaich et al., and others as necrosis or threatened necrosis in an area of injection.34–36 The algorithm offered by Hirsch et al. included two 325-mg enteric-coated aspirin, alternating topical nitroglycerin paste, and hot compresses to the affected area. In addition, 30 units of hyaluronidase is injected along the course of the artery involved.36 The patient showed resolution in 8 hours and, at 2 weeks, had no evidence of compromise.
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Plastic and Reconstructive Surgery • February 2014 HYALURONIDASE PREPARATIONS Hyaluronidase comes in several forms. The major categories are human recombinant and nonhuman (bovine and ovine). The preparations are similar, with the exception of source, preservative, concentration, and price; these differences are summarized in Table 2. Hyaluronidase preparations are very safe and have similar side-effect profiles, with a 0.1% rate of anaphylactic reaction. Because of this rate of anaphylaxis, patients should be given a test dose before full treatment.
USES OF HYALURONIDASE Use of injectables (botulinum toxin type A and fillers) for facial rejuvenation has become very popular. Hyaluronic acid–based fillers are rapidly increasing their market share year after year, primarily because of their good safety profile and predictable results. Careful injection technique and detailed knowledge of anatomy and filler can avoid many common complications. However, once complications occur, the provider should have a routine algorithm to resolve the complication or reduce the risk of harm to the patient.
ERRONEOUS PLACEMENT Superficial placement and/or excess placement occurs when filler is injected into the superficial dermis or too much filler is injected into one location. Superficial injection can occur if the visual cues are ignored during injection. Excess placement can be avoided by smooth, even deposition of filler. The easiest method is to develop a systematic method of placing filler to cover an area through linear threading, fanning, serial puncture, or crosshatching.3 If erroneous placement occurs, massage can often be used to spread/mold the filler to a more even shape. If massage does not help, a commercially available hyaluronidase of the provider’s choosing can be used to remove the hyaluronic acid filler. Hyaluronidase disperses rapidly in tissues, and in the dermis its activity is limited to 48 hours. It is these two properties that allow rapid degradation of
misplaced hyaluronic acid without risk of additional contour deformity.
GRANULOMATOUS INFECTION Hyaluronic acid–associated granulomatous infections typically present as red, nonpurulent bumps in the distribution of previous hyaluronic acid deposition. These infections can be treated initially with antibiotics and topical steroids, especially if the patient desires to maintain the fullness from the hyaluronic acid filler. However, if the infection is severe or the patient would like more immediate resolution, use of high-dose hyaluronidase has been shown to be effective.
IMPENDING NECROSIS Skin necrosis is the most severe of the complications that can occur with hyaluronic acid injection. To prevent vascular compromise, it is incumbent on the clinician to be aware of the anatomy and avoid inadvertent intraarterial or juxtaarterial injection. If vascular compromise occurs, time is of the essence to prevent necrosis. In addition to supportive measures (i.e., acetylsalicylic acid, warm compress, and nitroglycerin), 30 units of hyaluronidase should be injected along the course of the involved artery to allow restoration of flow (Fig. 1).
CONCLUSIONS Hyaluronic acid is a ubiquitous glycosaminoglycan that has been used for facial rejuvenation. Its popularity stems from its good safety profile and the ability to achieve reproducible results. Despite the safety of these agents, side effects can occur. Until the early 2000s, the clinician’s recourse for malplacement of hyaluronic acid fillers was massage, incision and drainage, oral antibiotics, oral steroids, and a tincture of time. Now, with the addition of hyaluronidase, clinicians have a safe and effective way of essentially erasing the effects of hyaluronic acid fillers. The rapid response of hyaluronidase can be particularly helpful in situations of skin compromise or even in the event of malposition or
Table 2. Comparison of Hyaluronidase Preparations Trade Name Amphadase Hydase Vitrase Hylenex
Source of Hyaluronidase Bovine Bovine Ovine Human recombinant
Date of FDA Approval
Currently Available
Available Dosage Form
October 26, 2004 No (2010) 150 USP units per ml, 2-ml vial October 25, 2005 No (2008) 150 USP units per ml, 2-ml vial May 5, 2004 Yes 200 USP units per ml, 2-ml vial December 2, 2005 Yes 150 USP units per ml, 2-ml vial
FDA, U.S. Food and Drug Administration; USP, U.S. Pharmacopeial Convention; N/A, not applicable.
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Preservative
Cost
Thimerosal N/A N/A N/A
N/A N/A $60.40/vial $51.67/vial
Volume 133, Number 2 • Changing Role of Hyaluronidase
Fig. 1. Impending skin necrosis. ASA, acetylsalicylic acid.
overfilling. Because of its good safety profile and effectiveness, clinicians using hyaluronic acid fillers should keep a hyaluronidase of their choosing on site to thwart the most severe complications. Rod J. Rohrich, M.D. Department of Plastic Surgery University of Texas Southwestern Medical Center 1801 Inwood Road Dallas, Texas 75390-9132 [email protected]
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purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol. 2005;140:573–584. 10. Amphastar Pharmaceuticals. Amphadase (hyaluronidase) package insert. Rancho Cucamonga, Calif: Amphastar Pharmaceuticals, Inc.; 2005. 11. Baxter Healthcare. Hylenex (hyaluronidase) package insert. San Diego, Calif: Baxter Healthcare Corp; 2006. 12. PrimaPharm. Hydase (hyaluronidase) package insert. San Diego, Calif: PrimaPharm; 2005. 13. ISTA Pharmaceuticals. Vitrase (hyaluronidase) package insert. Irvine, Calif.: ISTA Pharmaceuticals, Inc.; 2007. 14. Constans T, Dutertre JP, Frogé E. Hypodermoclysis in dehydrated elderly patients: Local effects with and without hyaluronidase. J Palliat Care 1991;7:10–12. 15. Pirrello RD, Ting Chen C, Thomas SH. Initial experiences with subcutaneous recombinant hyaluronidase. J Palliat Med. 2007;10:861–864. 16. Kallio H, Paloheimo M, Maunuksela EL. Hyaluronidase as an adjuvant in bupivacaine-lidocaine mixture for retrobulbar/peribulbar block. Anesth Analg. 2000;91:934–937. 17. Smith KJ, Skelton HG, Turiansky G, et al. Hyaluronidase enhances the therapeutic effect of vinblastine in intralesional treatment of Kaposi’s sarcoma. J Am Acad Dermatol. 1997;36:239–242. 18. Bocci V, Muscettola M, Naldini A, Bianchi E, Segre G. The lymphatic route: II. Pharmacokinetics of human recombinant interferon-alpha 2 injected with albumin as a retarder in rabbits. Gen Pharmacol. 1986;17:93–96. 19. Houck J, Chang C. Permeability factor contaminating hyaluronidase preparations. Inflammation 1979;3:447–451. 20. Sasson M, Shvartzman P. Hypodermoclysis: An alternative infusion technique. Am Fam Physician 2001;64:1575–1578. 21. Bellin MF, Jakobsen JA, Tomassin I, et al. Contrast medium extravasation injury: Guidelines for prevention and management. Eur Radiol. 2002;12:2807–2812. 22. Marcia L, Buck PD. Treatment of intravenous extravasations. Pediatr Pharmacother. 1998;4:1–2. 23. Zimmet SE. Hyaluronidase in the prevention of sclerotherapy-induced extravasation necrosis: A dose-response study. Dermatol Surg. 1996;22:73–76. 24. Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous phenytoin extravasation. J Child Neurol. 1998;13:246–247.
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32. Cohen JL. Understanding, avoiding, and managing der mal filler complications. Dermatol Surg. 2008;34(Suppl 1):S92–S99. 33. Klein AW. Granulomatous foreign body reaction against hyaluronic acid. Dermatol Surg. 2004;30:1070. 34. Inoue K, Sato K, Matsumoto D, Godna K, Yoshimura K. Arterial embolization and skin necrosis of the nasal ala following injection of dermal fillers. Plast Reconstr Surg. 2008;121:127e–128e. 35. Glaich AS, Cohen JL, Goldberg LH. Injection necrosis of the glabella: Protocol for prevention and treatment after use of dermal fillers. Dermatol Surg. 2006;32:276–281. 36. Hirsch RJ, Cohen JL, Carruthers JD. Successful management of an unusual presentation of impending necrosis following a hyaluronic acid injection embolus and a proposed algorithm for management with hyaluronidase. Dermatol Surg. 2007;33:357–360.
